Restoration of physiological aortic hemodynamics is a crucial therapeutic target after transcatheter aortic valve implantation (TAVI). However, quantifying this restoration is challenging, particularly using conventional markers. This study presents a novel, unsupervised approach based on proper orthogonal decomposition (POD), suitable for holistic characterization of patient-specific aortic flow field and their association with procedural outcome. Patients (n = 8) with severe aortic valve stenosis (AS) undergoing TAVI were studied. Three metrics were evaluated: patient-specific composite cardiovascular stress signature, pre-procedural free hemoglobin levels and degree of flow restoration. Flow restoration was quantified using POD-based similarity measures (Euclidean distances and Dynamic Time Warping), and compared with conventional hemodynamic markers, i.e. shear stresses, helicity and turbulence production. Unsupervised clustering was applied to explore agreement with biochemical patterns and clinical outcomes. POD identified coherent flow structures and enabled quantification of restoration relative to healthy references. POD-based markers provided more clinically interpretable groupings than conventional measures in this cohort. Patients with low restoration exhibited more pathological composite cardiovascular stress signatures and adverse outcomes during short-term follow-up. POD-based flow analysis provides a holistic and interpretable quantification of post-TAVI aortic hemodynamics. In the given cohort, the method showed agreement with biochemical patterns and clinical outcomes, highlighting its potential to complement conventional hemodynamic and procedural assessment.

IntroductionAbdominal aortic aneurysms and dissections (AAA/AD) are vascular disorders with high mortality due to aortic ruptures. Critical pathomechanisms involve immune cell infiltration and degradation of the vascular extracellular matrix (ECM). Hyaluronan (HA), a major constituent of the ECM synthesized by three HA synthase isoenzymes (HAS1-3), plays a role in both processes. Specifically, HAS3 is crucially involved in inflammatory conditions. Here, we aimed to elucidate the role of HAS3-derived HA in AAA/AD.MethodsMice double-deficient for apolipoprotein E and Has3 (Apoe/Has3-DKO) and littermate controls (Apoe-KO) were studied in a model of angiotensin II (AngII)-induced AAA/AD.ResultsHas3 deficiency improved survival in Apoe/Has3-DKO mice via reducing aortic ruptures. This was associated with decreased monocyte infiltration into the vessel wall. Aortic RNA-Seq analysis indicated disturbed immune cell adhesion and diapedesis. Transfer of Apoe-deficient bone marrow into Apoe/Has3-DKO mice largely normalized the Apoe/Has3-DKO phenotype. While gene expression in endothelial cells (ECs) was not affected, AngII-induced upregulation of proinflammatory cytokines, adhesion receptors and the HA receptor CD44 was attenuated in Apoe/Has3-DKO monocytes. This reduced CD44 cell surface expression in Apoe/Has3-double-deficient monocytes, ultimately inhibiting their in vitro transmigration.DiscussionOur results show that HAS3 plays a key role in AAA/AD formation and suggest the HAS3/CD44 axis as promising therapeutic target to reduce monocyte recruitment and aortic rupture.

Aims: Left atrial (LA) enlargement marks impaired cardiac filling and predicts future cardiovascular events. Dietary flavanols have been shown to reduce cardiovascular mortality, despite uncertain underlying mechanisms. In this study, we hypothesized that flavanol intake reduces LA volume in older individuals without cardiovascular diseases. Methods: In a substudy of the randomized, double-blinded Healthy Aging Through Dietary Intervention trial (NCT05782309), we investigated the effects of cocoa flavanols on cardiac volumetry and diastolic function in healthy older individuals. LA and left-ventricular (LV) volumes as well as strain rates were measured by high-resolution cardiac magnetic resonance imaging before and after flavanol intake. Results: Sixty-three participants (59% male) aged ≥ 55 years received either 500 mg cocoa flavanols (containing 80 mg (-)-epicatechin) originating from cocoa extract (n = 30) or a control (n = 33) twice daily for 30 days. Flavanol intake counteracted subclinical cardiac dysfunction, evidenced by a 12.6 ± 3.5% reduction in maximal LA volume (p = 0.0063) and LA volume index (p = 0.0067) and ∼4.4 ± 1.9% reduction in LV end-diastolic volume (LVEDV) (p = 0.049) and LVEDV index (p = 0.041). Flavanol intake did not influence strain, strain rate, and systolic function parameters, while the systolic blood pressure decreased by 7 mmHg [∼4.7 ± 1.9% (p = 0.04)]. Blood pressure dynamics, gender or age of participants in the intervention group were not associated with LA volumetric changes. Conclusion: We provide evidence that cocoa flavanol intake mitigates early changes of diastolic dysfunction by reversing left atrial and left ventricular remodeling, thus providing novel insights into the mechanisms behind the beneficial cardiovascular effect of flavanol intake. The clinical trial registry number is NCT05782309 (https://clinicaltrials.gov).

Aortic stenosis (AS) leads to alterations of supra-valvular flow patterns which can cause increased damage of red blood cell (RBC) membranes. We investigated these patient specific patterns of a severe AS patient and their reversal in healthy flow through a 4D Flow MRI-based CFD methodology. Computational models of subject-specific aortic geometries were created using in-vivo medical imaging data. Temporally and spatially resolved boundary conditions derived from 4D Flow MRI were implemented for an AS patient and a healthy subject. After validation of the in-silico results with in-vivo data, a healthy inflow profile was set for the AS patient in the CFD model. Pathological versus healthy flow fields were compared regarding their blood flow characteristics, i.e., shear stresses on RBCs and helicity. The accuracy of the 4D Flow MRI-based CFD model was proven with excellent agreement between in-vivo and in-silico velocity fields and R² = 0.9. A pathological high shear stress region in the bulk flow was present during late systole with an increase of 125% compared to both healthy flow. The physiological bihelical structure with predominantly right-handed helices vanished for the pathological state. Instead, a left-handed helix appeared, accompanied by an overall increase in turbulent kinetic energy in areas of accumulated left-handed helicity. The validated 4D Flow MRI-based CFD model identified marked differences between AS and healthy flow. It suggests that altered turbulent and helical structures in the bulk flow are the cause for increased, potentially damaging forces acting upon RBCs in AS.

Purpose: Outlet boundary conditions (OBC) play a pivotal role in all simulations of vascular flow. However, previous investigations of OBC impact on numerical aortic flow simulations were not yet comprehensive for the entirety of hemodynamic characteristics. They mainly investigated near-wall properties and velocity in physiological flow. Therefore, the aim of this work was to expand the sensitivity assessment to hemodynamic markers in the bulk flow to the choice of OBC for a physiological and pathological aortic flow field. Material and methods: Image-based computational models of subject-specific aortic geometries were created. Temporally and spatially resolved inlet velocity profiles derived from 4D Flow MRI were implemented. Three types of OBCs were compared: zero pressure, loss coefficients and three-element Windkessel. Their influence on velocity, near-wall properties and bulk flow quantities were analyzed. Results: Velocity and near-wall parameters in the ascending aorta are largely insensitive to the OBC choice. However, bulk flow parameters, in particular the helicity field, are highly sensitive throughout the entire aortic domain with differences of up to 600 % between models. The relative sensitivity to OBC drops for pathological flows, as the influence of more complex inlet profiles increases. Conclusion: While the sensitivity of velocity and near-wall parameters to OBC choice is insignificant when only the ascending aorta is assessed, our study proposes a more thorough discernment once bulk flow parameters are of interest. Different degrees of boundary condition complexity are required to determine the hemodynamic properties of interest accurately. A support tool is presented to determine the case-dependent minimum requirement for inlet and outlet boundary conditions.

BACKGROUND:Aortic valve disease (AVD) is associated with high mortality and morbidity. To date, there is no pharmacological therapy available to prevent AVD progression. Because valve calcification is the hallmark of AVD and S1P (sphingosine-1-phosphate) plays an important role in osteogenic signaling, we examined the role of S1P signaling in aortic stenosis disease. METHODS:AVD progression and its consequences for cardiac function were examined in a murine wire injury-induced AVD model with and without pharmacological and genetic modulation of S1P production, degradation, and receptor signaling. S1P was measured by liquid chromatography-mass spectrometry. Calcification of human valvular interstitial cells and their response to biomechanical stress were analyzed in the context of S1P signaling. Human explanted aortic valves from patients undergoing aortic valve replacement and cardiovascular magnetic resonance imaging were analyzed for S1P by liquid chromatography-mass spectrometry. RESULTS:Raising S1P concentrations in mice with injury-induced AVD by pharmacological inhibition of its sole degrading enzyme S1P lyase vastly enhanced AVD progression and impaired cardiac function resembling human disease. In contrast, low S1P levels caused by SphK1 (sphingosine kinase 1) deficiency potently attenuated AVD progression. We found S1P/S1PR2 (S1P receptor 2) signaling to be responsible for the adverse S1P effect because S1PR2-deficient mice were protected against AVD progression and its deterioration by high S1P. It is important to note that pharmacological S1PR2 inhibition administered after wire injury successfully prevented AVD development. Mechanistically, biomechanical stretch stimulated S1P production by SphK1 in human valvular interstitial cells as measured by C17-S1P generation, whereas S1P/S1PR2 signaling induced their osteoblastic differentiation and calcification through osteogenic RUNX2/OPG signaling and the GSK3β-Wnt-β-catenin pathway. In patients with AVD, stenotic valves exposed to high wall shear stress had higher S1P content and increased SphK1 expression. CONCLUSIONS:Increased systemic or local S1P levels lead to increased valvular calcification. S1PR2 antagonists and SphK1 inhibitors may offer feasible pharmacological approaches to human AVD in prophylactic, disease-modifying or relapse-preventing manners.

BACKGROUND AND PURPOSE:Remote ischaemic preconditioning (rIPC) for cardioprotection is severely impaired in diabetes, and therapeutic options to restore it are lacking. The vascular endothelium plays a key role in rIPC. Given that the activity of endothelial nitric oxide synthase (eNOS) is inhibited by proline-rich tyrosine kinase 2 (Pyk2), we hypothesized that pharmacological Pyk2 inhibition could restore eNOS activity and thus restore remote cardioprotection in diabetes. EXPERIMENTAL APPROACH:New Zealand obese (NZO) mice that demonstrated key features of diabetes were studied. The consequence of Pyk2 inhibition on endothelial function, rIPC and infarct size after myocardial infarction were evaluated. The impact of plasma from mice and humans with or without diabetes was assessed in isolated buffer perfused murine hearts and aortic rings. KEY RESULTS:Plasma from nondiabetic mice and humans, both subjected to rIPC, caused remote tissue protection. Similar to diabetic humans, NZO mice demonstrated endothelial dysfunction. NZO mice had reduced circulating nitrite levels, elevated arterial blood pressure and a larger infarct size after ischaemia and reperfusion than BL6 mice. Pyk2 increased the phosphorylation of eNOS at its inhibitory site (Tyr656), limiting its activity in diabetes. The cardioprotective effects of rIPC were abolished in diabetic NZO mice. Pharmacological Pyk2 inhibition restored endothelial function and rescued cardioprotective effects of rIPC. CONCLUSION AND IMPLICATIONS:Endothelial function and remote tissue protection are impaired in diabetes. Pyk2 is a novel target for treating endothelial dysfunction and restoring cardioprotection through rIPC in diabetes.

Abstract Background Enlargement of the left atrium (LA) predicts future cardiovascular events. Current guidelines recommend cocoa flavanol (CF) intake as it provides cardiovascular and metabolic benefits, although underlying mechanisms are not fully revealed. In this study, we hypothesized that CF intake reverses LA enlargement as a surrogate marker for diastolic dysfunction in elderly individuals without cardiovascular diseases. Methods and Results In a randomized, double-blinded trial, we investigated the effects of CF on systolic and diastolic heart function in healthy elderly individuals. Precise assessment of left-atrial and left-ventricular volume as well as strain rates, all together as emblems of early subclinical cardiac impairment, and markers of systolic function were measured by high-resolution cardiac magnetic resonance (CMR) imaging before and after CF intake. Sixty-three participants (59% male) aged ≥ 55 years received either 500 mg CF (n=30) or a placebo (n=33) twice daily for 30 days. CF counteracted subclinical cardiac dysfunction, evidenced by a reduction in maximal LA volume and LA volume index by 12.6±3.5% (p=0.0063 and p=0.0067) and LV end-diastolic volume (LVEDV) and LVEDV index by ~4.9±1.9% (p=0.049 and p=0.0413). CF intake did not influence strain, strain rate, and systolic function parameters, while the systolic blood pressure decreased by 7 mmHg [~4.7±1.9% (p=0.04)]. Conclusion We provide evidence that CF intake mitigates early changes of diastolic dysfunction and improves cardiovascular health by reversing left atrial and left ventricular remodeling. Cocoa flavanol consumption may prevent age-related cardiac changes in healthy elderly individuals and promote a health span free from cardiovascular diseases.

BACKGROUND:Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS:We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system. RESULTS:In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress. CONCLUSIONS:AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT05603520 and NCT01805739.

BACKGROUND: Recent research indicates that there is a high prevalence of heart failure with preserved ejection fraction in patients with peripheral artery disease. We hypothesized that endovascular treatment (EVT) of flow-limiting peripheral stenosis improves left ventricular (LV) diastolic function. METHODS: Thirty patients with symptomatic peripheral artery disease and heart failure with preserved ejection fraction according to Heart Failure Association−preserved ejection fraction score who were scheduled for EVT or angiography were investigated at baseline, the day after EVT (n=25) or angiography (control, n=5), and at 4 months follow-up. Peripheral hemodynamics were determined by the total peripheral resistance, common femoral artery flow, and ankle brachial index. Aortic function was measured by arterial compliance, augmentation index, and pulse wave velocity. Aortic pulsatile load was estimated as the characteristic impedance of the proximal aorta and the magnitude of wave reflection (reflection coefficient). LV mass index, LV mean wall thickness, and systolic and diastolic function were assessed using echocardiography. Patient-centered outcomes were treadmill walking distance and New York Heart Association class. RESULTS: After EVT, peripheral hemodynamics changed significantly with a decrease in total peripheral resistance and an increase in common femoral artery flow and ankle brachial index. Aortic function improved after EVT, with significantly reduced augmentation index and pulse wave velocity and increased compliance immediately and at follow-up, resulting in a reduction in aortic pulsatile load (characteristic impedance of the proximal aorta and reflection coefficient). Concurrently, LV diastolic function improved after EVT compared with control, acutely and at follow-up, with increased septal and lateral e´ velocities and decreased E / e ´ and left atrial volume index. The LV mass index and LV mean wall thickness decreased at follow-up. The New York Heart Association class and treadmill walking distance improved post-EVT at follow-up. Augmentation index, pulse wave velocity, and arterial compliance were identified as independent contributors to E / e ´. CONCLUSIONS: Endovascular treatment of flow-limiting iliofemoral stenosis reduces aortic pulsatile load and concurrently lowers total peripheral resistance. This beneficial effect is associated with an acute and sustained improvement of left ventricular diastolic function. REGISTRATION: URL: http://www.clinicaltrials.gov ; Unique identifier: NCT02728479.

Objectives. Dynamic Coronary Roadmap (DCR) is a software tool that creates a real-time dynamic coronary artery overlay on fluoroscopic images. The efficacy of DCR in significantly reducing contrast medium use during percutaneous coronary interventions (PCI) has previously been shown. In this study, we aimed to determine if DCR is equally effective irrespective of the performing investigator's experience level. Methods. In this sub -analysis of a monocentric, open -label, randomized trial, 130 patients with hemodynamic relevant coronary type A and B lesions were randomized and contrast medium use was conducted with (+) or without (-) DCR software. PCI was randomly allocated and performed by an investigator with high (A) or medium (B) experience level. Results. Overall, contrast medium use was significantly reduced by both investigators in the +DCR group, and Investigator B used significantly less contrast medium with the software than Investigator A. The DCR software was not accompanied by increased radiation exposure for the patients or the teams. On the contrary, dose area product was reduced by both investigators, but was significantly reduced by the highly experienced investigator when using DCR. Fluoroscopy time was not different between investigators. Procedural success was 100%. Serious in -hospital adverse events were not observed. One of Investigator A's patients suffered from post -procedural acute kidney injury in the -DCR group. Conclusions. DCR significantly reduces contrast medium use during PCI irrespective of investigator's experience level.

Objective Inflammation is a critical process during the progressive development and complication of abdominal aortic aneurysm. The co-stimulatory dyad CD40-CD40L is a major driver of inflammation and modulates immune responses. This study evaluates the potential of a small molecule inhibitor, which blocks the interaction between CD40 and tumor necrosis factor (TNF) receptor-associated factor (TRAF)-6, referred to as TRAF-STOP, in the early and later phase during AAA progression. Methods and results AAAs were induced in C57BL/6J mice by infrarenal aortic porcine pancreatic elastase infusion for 7, 14 or 28 days. Inhibition of CD40 signaling by TRAF-STOP resulted in less severe AAA formation and reduced the incidence of AAA development. TRAF-STOP treatment attenuated aortic structural remodeling, characterized by a reduced elastic fiber degradation, lowered expression of matrix metalloproteinase (MMP)-2 and MMP9, as well as preserved collagen type IV content in aneurysmal tissue. Furthermore, this is accompanied by the reduction of key pro-inflammatory genes such as TNFα. Conclusion Pharmacological inhibition of CD40-TRAF6 signaling protects from adverse aortic structural remodeling during the early phase of AAA progression representing a translational strategy to limit progression of human AAA disease.

Aims: Identifying patients who may benefit from mechanical circulatory support (MCS) after out-of-hospital cardiac arrest (OHCA) and return of spontaneous circulation (ROSC) remains challenging; thus, a search for helpful biomarkers is warranted. We aimed to evaluate phosphate and lactate levels on admission regarding their associations with survival with and without MCS. Methods: In 224 OHCA patients who achieved ROSC, the initial phosphate and lactate levels were investigated to discriminate in-hospital mortality by receiver operating characteristic (ROC) curves. According to the Youden Index (YI) from the respective ROC, the groups were risk stratified by both biomarkers, and 30-day mortality was analyzed in patients with and without MCS. Results: Within the entire collective, MCS was not associated with a better chance of survival. Both phosphate and lactate level elevations showed good yet comparable discriminations to predict mortality (areas under the curve: 0.80 vs. 0.79, p = 0.74). In patients with initial phosphate values > 2.2 mmol/L (>YI), 30-day mortality within the MCS cohort was lower (HR 2.3, 95% CI: 1.4–3.7; p = 0.0037). In patients with lower phosphate levels and groups stratified by lactate, 30-day mortality was similar in patients with and without MCS. Conclusions: We found a significant association between survival and MCS therapy in patients with phosphate levels above 2.2 mmol/L (Youden Index), and a similar discrimination of patient overall survival by lactate and phosphate. Prospective studies should assess the possible independent prognostic value of phosphate and its clearance for MCS efficiency.

Background: The transradial approach for coronary angiography is associated with fewer complications and preferred over the femoral approach. Injury to the radial artery (RA) endothelium elicits intimal hyperplasia, possibly resulting in total occlusion and limb functional decline. Flavanols are known to improve endothelial function. Effects on arterial remodeling after mechanical injury are unknown. Objective: To investigate the effects of cocoa flavanols on (a) intimal hyperplasia and (b) endothelial functional recovery after mechanical vascular wall injury through transradial coronary angiography (TCA). Methods: Primary endpoint in this double-blind, randomized, controlled trial was RA intima-media thickness (IMT) after 6 months follow-up (FU). Secondary endpoints were RA flow-mediated vasodilation (FMD) and fractional diameter change (Fdc). Further luminal diameter and circulating endothelial microparticles (EMP) were assessed. Thirty-six male patients undergoing elective TCA were included. Flavanol or matched placebo supplementation started 7 days prior TCA (cocoa flavanol 1000 mg day-1) for 14 days. Four measurements spanned three periods over 6-moths-FU. Results: TCA induced sustained intimal hyperplasia in the placebo-, but not in the flavanol-group (IMT 0.44 ± 0.01 vs. 0.37 ± 0.01 mm, p = 0.01). FMD decreased after TCA in both groups, but recovered to baseline after 6 months in the flavanol group only. Fdc acutely decreased, EMPs increased in the placebo-, not in the flavanol -group. Luminal diameter remained unchanged in both groups. Conclusion: Peri-interventional cocoa flavanol supplementation prevents long-term intima media thickening and endothelial dysfunction 6 months after TCA opening the perspective for dietary interventions to mitigate endothelial cell damage and intimal hyperplasia after mechanical injury.

Abstract Background/Introduction Dynamic Coronary Roadmap (DCR) is a software tool that creates a real-time dynamic coronary artery overlay on the fluoroscopic image. Its efficacy in significantly reducing contrast medium use during percutaneous coronary interventions (PCI) has already been shown. Purpose The purpose of this study is to investigate whether the positive effects of DCR persist irrespective of the investigator’s experience level. Methods In this sub-analysis of a monocentric, open-label, randomized trial, 130 patients with hemodynamically relevant coronary type A and B lesions were randomized (1:1 ratio) and conducted with or without DCR software. PCI was randomly allocated and performed by an investigator with high (A) or medium (B) experience level. Results Overall, the primary endpoint contrast medium use was significantly reduced by both investigators in the +DCR group (Investigator A: –DCR 68.62 +/- 23.86ml vs. +DCR 43.39 +/- 21.91ml; Investigator B: –DCR 70.80 +/- 31.77ml vs. +DCR 29.46 +/- 12.26ml, p < 0.0001). With the software, Investigator B used significantly less contrast medium than Investigator A (p = 0.0468). The DCR software is not accompanied by increased radiation exposure for the patients or the teams. On the contrary, the dose area product was reduced by both investigators but was significantly reduced with DCR in the highly experienced investigator (Investigator A: –DCR 2415.25 +/- 1413.30 cGycm² vs. +DCR 1727.17 +/- 1148.69 cGycm², p = 0.0284). Fluoroscopy time was not different between investigators. Procedural success was 100%. Serious in-hospital adverse events were not observed. One patient of Investigator A suffered from post-procedural acute kidney injury in the –DCR group. Conclusion(s) DCR significantly reduces contrast medium use during PCI irrespective of the investigator’s experience level. Efficacy and safety do not differ between investigators’ experience levels. Whether these excellent results can also be translated into more complex lesion settings has to be evaluated in future trials.Operating principle of DCRPrimary and secondary endpoints

Background: Loss of functional capacity is one of the hallmarks in cardiovascular aging. Cocoa flavanols (CF) exert favorable effects on endothelial function, blood pressure, and inflammation. These cardiovascular health markers worsen with increasing age and limit functional exercise capacity. Aim: To investigate the effect of CF on cardiorespiratory-fitness in healthy elderly people. Methods: In a randomized, double-masked, placebo-controlled, parallel-group dietary intervention trial, 68 healthy elderly people (55-79 years, 28 female) received either 500 mg of CF or a nutrient-matched control capsule twice a day for 30 days. Primary endpoint was defined as peak oxygen consumption (VO2) in a cardiopulmonary exercise test (CPET). Secondary endpoints were oxygen pulse (VO2 per heart rate (HR)), resting blood pressure (BP), and resting vascular function. Results: After 30 days of CF intake peakVO2 increased by 190 ml min-1 (95% CI 1-371 ml min-1) and peakVO2 per kg by 2.5 ml (min kg)-1 (95% CI 0.30-4.2 ml (min kg)-1). O2-pulse increased by 1.7 ml (95% CI 0.29-3.2 ml) and max exercise capacity by 9.6 W (95% CI 2.1-17.7 W). CF decreased resting systolic and diastolic BP by 5.4 mmHg (95% CI -10.7 to -0.1 mmHg) and 2.9 mmHg (95% CI -5.5 to -0.4 mmHg), respectively. Flow-mediated vasodilation (FMD) increased by an absolute 1.3% (95% CI 0.76-1.79%) in the CF group. Indexes of pulmonary function were not affected. No changes for primary and secondary endpoints were detected in control. Conclusion: CF substantially improve markers of cardiorespiratory fitness in healthy elderly humans highlighting their potential to preserve cardiovascular health with increasing age.

Abstract Background There are several cardiovascular risk factors known to promote the development of AS, one of them being type 2 diabetes (T2D). T2D is increasingly recognized as a heterogenous disease, leading to the latest concept of five diabetes clusters based on clinical parameters. Until now, the impact of the respective clusters, especially insulin resistance in prediabetes, on valvular cells and therefore the development of AS is not clear. Purpose We hypothesize that insulin resistance, which is frequently underrated, features a specific pattern of aortic valve calcification characterized by an elevated degree of calcification. Methods In order to analyze the impact of diabetes on AS we examined 200 patients with severe AS, scheduled for a transcatheter aortic valve implantation (TAVI). With the exemption of previously diagnosed diabetics, we performed an oral glucose tolerance test (OGTT), identifying patients with prediabetes and T2D. Additionally, blood was drawn from all included patients 2-5 days after TAVI, depicting their metabolic condition and thereby assigning them to a diabetes cluster. These findings were subsequently correlated with data from computertomography in all patients pertaining the severity of the stenosis, including the Agatston score, which illustrates the aortic valve calcium burden. Results Following the hypothesis that the extent of insulin resistance impacts the aortic valve calcification, we correlated the HOMA-IR with the Agatston score, resulting in a weak non-significant linear correlation (r=-0.129, p = 0.097, n = 166). Therefore, increased insulin resistance has not been shown to be associated with increased aortic valve calcification. Moreover, no differences in the extent of calcification between diabetic, prediabetic and non-diabetic patients could be demonstrated (F (2, 147) = 0.410, p = 0.665). However, it was clearly striking that the majority of the patients examined had already developed prediabetes or diabetes (Non-Diabetic = 7.1%, Prediabetic = 34.6%, Diabetic = 58.2%, n= 182). Conclusion Although we were able to observe an increased rate in prediabetic and diabetic patients in our AS cohort, there was no significantly elevated aortic valve calcification in patients with pronounced insulin resistance. This suggests that insulin resistance might not directly impact valvular calcification but upstream processes in valvular cells predisposing for AS since the majority of AS patients in our cohort is (pre)diabetic.

Purpose: Although a moderate proportion of cardiac arrest (CA) patients achieve a return of spontaneous circulation (ROSC), few survive to discharge, mostly with poor neurological development. As serum phosphate levels were described as elevated after cardiopulmonary resuscitation (CPR), we asked whether these elevations would predict a higher risk of mortality and impaired neurological outcome in CA patients following ROSC. Methods: Initial serum phosphate levels, survival, and neurologic status at discharge of 488 non-traumatic CA patients treated at a single German hospital after achieving ROSC were analyzed. The cut-off value of phosphate for mortality prediction was determined using the receiver operator characteristic (ROC) curve, and patients were divided accordingly for comparison. Results were validated by analyzing phosphate levels in a multi-centric cohort containing 3299 CA patients from the eICU database of the United States. Results: In the German cohort, ROC analysis showed a 90% specificity for phosphate levels >2.7 mmol/L to predict mortality (AUC: 0.76, p < 0.0001), and phosphate level elevations were associated with higher in-hospital mortality (crude odds ratio 3.04, 95% CI 2.32 to 4.08). Patients with initial phosphate levels >2.7 mmol/L had significantly higher mortality in both analyzed collectives (p < 0.0001). Similarly, patients from the German cohort who initially had higher phosphate levels also showed a higher proportion of impaired neurological status at discharge and morphological signs of brain injury. Conclusions: In CA patients following ROSC, initial serum phosphate levels >2.7 mmol/L predict higher mortality and impaired neurological outcome. Our data suggests that phosphate determination might improve the preciseness of the overall and neurologic prognostication in patients after CPR following ROSC.

Aortic valve stenosis (AS) development is driven by distinct molecular and cellular mechanisms which include inflammatory pathways. Toll-like-receptor-3 (TLR3) is a lysosomal pattern-recognition receptor that binds double-stranded RNA and promotes pro-inflammatory cellular responses. In recent years, TLR3 has emerged as a major regulator of vascular inflammation. The exact role of TLR3 in the development of AS has not been investigated. Isolated human valvular interstitial cells (VICs) were stimulated with the TLR3-agonist polyIC and the resulting pro-inflammatory and pro-osteogenic response measured. Severe AS was induced in wildtype- and TLR3−/− mice via mechanical injury of the aortic valve with a coronary springwire. TLR3 activation was achieved by polyIC injection every 24 h after wire injury, while TLR3 inhibition was realized using Compound 4a (C4a) every 48 h after surgery. Endothelial mesenchymal transition (EndoMT) of human valvular endothelial cells (VECs) was assessed after polyIC stimulation. Stimulation of human VICs with polyIC promoted a strong inflammatory and pro-osteogenic reaction. Similarly, injection of polyIC marginally increased AS development in mice after wire injury. AS induction was significantly decreased in TLR3−/− mice, confirming the role of endogenous TLR3 ligands in AS pathology. Pharmacological inhibition of TLR3 with C4a not only prevented the upregulation of inflammatory cytokines and osteogenic markers in VICs, and EndoMT in VECs, but also significantly abolished the development of AS in vivo. Endogenous TLR3 activation significantly contributes to AS development in mice. Pharmacological inhibition of TLR3 with C4a prevented AS formation. Therefore, targeting TLR3 may be a viable treatment option.